Feedback Mechanism for an Injection Device

ABSTRACT

A feedback mechanism for an injection device that is configured to deliver a medicament to a user is described. The feedback mechanism comprises a piston and a fluid chamber, and the piston is adapted to move into the fluid chamber during use of the injection device. The feedback mechanism also has a damper that is arranged to damp movement of the piston, and an indicator that is arranged to provide feedback to the user after the piston has moved a pre-determined distance into the fluid chamber.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. patent application Ser.No. 16/346,250, filed on Apr. 30, 2019, which is the national stageentry of International Patent Application No. PCT/EP2017/076056, filedon Oct. 12, 2017, and claims priority to Application No. EP 16196676.7,filed on Nov. 1, 2016, the disclosures of which are incorporated hereinby reference.

TECHNICAL FIELD

The present disclosure relates to a feedback mechanism for an injectiondevice.

BACKGROUND

Injection devices, such as auto-injectors, typically have a syringe intowhich a plunger is pushed to dispense medicament from the syringe intothe patient via a needle. The injection process is completed when theplunger has been pushed the appropriate distance into the syringe. It isknown to provide a feedback mechanism for indicating to the user whenthe appropriate volume of medicament has been injected.

SUMMARY

It is an object of the present disclosure to provide a feedbackmechanism for an injection device that provides feedback to a user.

According to a first aspect, there is provided a feedback mechanism foran injection device, said injection device being configured to deliver amedicament to a user, the feedback mechanism comprising:

-   -   a piston and a fluid chamber, the piston being adapted to move        into the fluid chamber during use of the injection device;    -   a damper arranged to damp movement of the piston; and,    -   an indicator arranged to provide feedback to said user after the        piston has moved a pre-determined distance into the fluid        chamber.

The feedback mechanism may further comprise a biasing member arranged tourge the piston into the fluid chamber during use.

The damper may comprise a rotary agitator disposed within the fluidchamber, and wherein movement of the piston into the fluid chamber maycause rotation of the rotary agitator such that the movement of thepiston is damped by the rotary agitator.

The piston may comprise the rotatory agitator.

The piston may comprise a plate that extends across the fluid chamber,and the damper may comprise one or more orifices located in the platethrough which fluid flows as the piston moves into the fluid chamber.

The feedback mechanism may further comprise a recipient chamber intowhich fluid is urged as the piston moves into the fluid chamber, andwherein the damper may comprise an orifice arranged between the fluidchamber and the recipient chamber.

The recipient chamber may comprise a slider that is moved by fluidpassing into the recipient chamber, and wherein the slider may beconfigured to engage the indicator after the slider has moved apredetermined distance, and wherein the indicator may provide feedbackto said user after being engaged.

The indicator may be disposed between the piston and a part of saidinjection device, such that movement of the piston into the fluidchamber causes the indicator to be engaged by the piston and/or saidpart of said injection device, and wherein the indicator may providefeedback to said user after being engaged.

The indicator may comprise a sound generator that generates an audiblesound.

The sound generator may comprise a pre-stressed element that generatesan audible sound when deflected.

According to a further aspect, there is also provided an injectiondevice comprising a medicament delivery mechanism comprising a reservoirand a plunger that moves to displace medicament from the reservoir fordelivery to a user during use of the injection device; and, the feedbackmechanism described above.

The injection device may further comprise a biasing member arranged topush the plunger into the reservoir during use.

The biasing member may be arranged to act on the piston, and wherein thepiston and plunger may be arranged such that force applied to the pistonis transferred to the plunger via the fluid chamber.

The damper may comprise an orifice formed in the plunger.

The injection device may further comprise a housing, and wherein thedamper may comprise an orifice formed in the housing.

The indicator may comprise a pre-stressed element that generates anaudible sound when deflected, the pre-stressed element being mounted tothe plunger and arranged to be deflected as the plunger moves todisplace medicament.

The plunger may comprise an arm to which the pre-stressed element ismounted, the arm being arranged to engage a feature of the piston as thepiston moves into the fluid chamber, and wherein the arm is arranged todeflect the pre-stressed element after engaging with the feature of thepiston.

The injection device may be configured such that the piston beginsmoving into the fluid chamber after the plunger has moved apre-determined distance into the reservoir.

The injection device may further comprise a locking mechanism arrangedto hold the piston until the plunger has reached a pre-determinedposition, and to then release the piston such that the piston can moveinto the fluid chamber.

The reservoir may contain a medicament.

According to a further aspect, there is also provided a method of usingan injection device, the method comprising:

-   -   delivering a medicament to a user;    -   moving a piston into a fluid chamber;    -   damping said movement of the piston; and,    -   providing feedback to said user after the piston has moved a        pre-determined distance into the fluid chamber.

These and other aspects will be apparent from and elucidated withreference to the embodiments described hereinafter.

BRIEF DESCRIPTION OF THE FIGURES

Embodiments will now be described, by way of example only, withreference to the accompanying drawings, in which:

FIG. 1A is a schematic side view of an injection device and a removablecap;

FIG. 1B is a schematic side view of the injection device of FIG. 1A,with the cap removed from the housing;

FIG. 2A is a cross-sectional side view of an injection device having adamper and an indicator, shown before the injection device has beenused;

FIG. 2B is a cross-sectional side view of the injection device of FIG.2A, after the injection device has been used;

FIG. 3A is a cross-sectional side view of an injection device having adamper, an indicator and a locking mechanism, shown before the injectiondevice has been used;

FIG. 3B is a magnified cross-sectional side view of the lockingmechanism of the injection device of FIG. 3A;

FIG. 4 is a cross-sectional side view of another injection device havinga damper and an indicator, shown before the injection device has beenused;

FIG. 5A is a cross-sectional side view of another injection devicehaving a damper and an indicator, shown before the injection device hasbeen used;

FIG. 5B is a cross-sectional side view of the injection device of FIG.5A, after the injection device has been used;

FIG. 6A is a cross-sectional side view of another injection devicehaving a damper and an indicator, shown before the injection device hasbeen used;

FIG. 6B is a cross-sectional side view of the injection device of FIG.6A, after the injection device has been used;

FIG. 7A is a cross-sectional side view of another injection devicehaving a damper and an indicator, shown before the injection device hasbeen used; and,

FIG. 7B is a cross-sectional side view of the injection device of FIG.6A, after the injection device has been used.

DETAILED DESCRIPTION

A drug delivery device, as described herein, may be configured to injecta medicament into a patient. For example, delivery could besub-cutaneous, intra-muscular, or intravenous. The user of such a devicecould be a patient or care-giver, such as a nurse or physician, and caninclude various types of safety syringe, pen-injector, or auto-injector.The device can include a cartridge-based system that requires piercing asealed ampule before use. Volumes of medicament delivered with thesevarious devices can range from about 0.5 ml to about 2 ml. Yet anotherdevice can include a large volume device (“LVD”) or patch pump,configured to adhere to a patient's skin for a period of time (e.g.,about 5, 15, 30, 60, or 120 minutes) to deliver a “large” volume ofmedicament (typically about 2 ml to about 10 ni).

In combination with a specific medicament, the presently describeddevices may also be customized in order to operate within requiredspecifications. For example, the device may be customized to inject amedicament within a certain time period (e.g., about 3 to about 20seconds for auto-injectors, and about 10 minutes to about 60 minutes foran LVD). Other specifications can include a low or minimal level ofdiscomfort, or to certain conditions related to human factors,shelf-life, expiry, biocompatibility, environmental considerations, etc.Such variations can arise due to various factors, such as, for example,a drug ranging in viscosity from about 3 cP to about 50 cP.Consequently, a drug delivery device will often include a hollow needleranging from about 25 to about 31 Gauge in size. Common sizes are 17 and29 Gauge.

The delivery devices described herein can also include one or moreautomated functions. For example, one or more of needle insertion,medicament injection, and needle retraction can be automated. Energy forone or more automation steps can be provided by one or more energysources. Energy sources can include, for example, mechanical, pneumatic,chemical, or electrical energy. For example, mechanical energy sourcescan include springs, levers, elastomers, or other mechanical mechanismsto store or release energy. One or more energy sources can be combinedinto a single device. Devices can further include gears, valves, orother mechanisms to convert energy into movement of one or morecomponents of a device.

The one or more automated functions of an auto-injector may each beactivated via an activation mechanism. Such an activation mechanism caninclude an actuator, for example, one or more of a button, a lever, aneedle sleeve, or other activation component. Activation of an automatedfunction may be a one-step or multi-step process. That is, a user mayneed to activate one or more activation components in order to cause theautomated function. For example, in a one-step process, a user maydepress a needle sleeve against their body in order to cause injectionof a medicament. Other devices may require a multi-step activation of anautomated function. For example, a user may be required to depress abutton and retract a needle shield in order to cause injection.

In addition, activation of one automated function may activate one ormore subsequent automated functions, thereby forming an activationsequence. For example, activation of a first automated function mayactivate at least two of needle insertion, medicament injection, andneedle retraction. Some devices may also require a specific sequence ofsteps to cause the one or more automated functions to occur. Otherdevices may operate with a sequence of independent steps.

Some delivery devices can include one or more functions of a safetysyringe, pen-injector, or auto-injector. For example, a delivery devicecould include a mechanical energy source configured to automaticallyinject a medicament (as typically found in an auto-injector) and a dosesetting mechanism (as typically found in a pen-injector).

According to some embodiments of the present disclosure, an exemplarydrug delivery device 10 is shown in FIGS. 1A & 1B. Device 10, asdescribed above, is configured to inject a medicament into a patient'sbody. Device 10 includes a housing 11 which typically contains a syringe18 containing the medicament to be injected and the components requiredto facilitate one or more steps of the delivery process. A cap 12 isalso provided that can be detachably mounted to the housing 11.Typically, a user must remove cap 12 from housing 11 before device 10can be operated.

As shown, housing 11 is substantially cylindrical and has asubstantially constant diameter along the longitudinal axis A-A. Thehousing 11 has a distal region D and a proximal region P. The term“distal” refers to a location that is relatively closer to a site ofinjection, and the term “proximal” refers to a location that isrelatively further away from the injection site.

Device 10 can also include a needle sleeve 19 coupled to housing 11 topermit movement of sleeve 19 relative to housing 11. For example, sleeve19 can move in a longitudinal direction parallel to longitudinal axisA-A. Specifically, movement of sleeve 19 in a proximal direction canpermit a needle 17 to extend from distal region D of housing 11.

Insertion of needle 17 can occur via several mechanisms. For example,needle 17 may be fixedly located relative to housing 11 and initially belocated within an extended needle sleeve 19. Proximal movement of sleeve19 by placing a distal end of sleeve 19 against a patient's body andmoving housing 11 in a distal direction will uncover the distal end ofneedle 17. Such relative movement allows the distal end of needle 17 toextend into the patient's body. Such insertion is termed “manual”insertion as needle 17 is manually inserted via the patient's manualmovement of housing 11 relative to sleeve 19.

Another form of insertion is “automated”, whereby needle 17 movesrelative to housing 11. Such insertion can be triggered by movement ofsleeve 19 or by another form of activation, such as, for example, abutton 13. As shown in FIGS. 1A & 1B, button 13 is located at a proximalend of housing 11. However, in other embodiments, button 13 could belocated on a side of housing 11.

Other manual or automated features can include drug injection or needleretraction, or both. Injection is the process by which a bung 14 ismoved from a proximal location within a syringe 18 to a more distallocation within the syringe 18 in order to force a medicament from thesyringe 18 through needle 17. In some embodiments, a drive spring (notshown) is under compression before device 10 is activated. A proximalend of the drive spring can be fixed within proximal region P of housing11, and a distal end of the drive spring can be configured to apply acompressive force to a proximal surface of bung 14. Followingactivation, at least part of the energy stored in the drive spring canbe applied to the proximal surface of bung 14. This compressive forcecan act on bung 14 to move it in a distal direction. Such distalmovement acts to compress the liquid medicament within the syringe 18,forcing it out of needle 17.

Following injection, needle 17 can be retracted within sleeve 19 orhousing 11. Retraction can occur when sleeve 19 moves distally as a userremoves device 10 from a patient's body. This can occur as needle 17remains fixedly located relative to housing 11. Once a distal end ofsleeve 19 has moved past a distal end of needle 17, and needle 17 iscovered, sleeve 19 can be locked. Such locking can include locking anyproximal movement of sleeve 19 relative to housing 11.

Another form of needle retraction can occur if needle 17 is movedrelative to housing 11. Such movement can occur if the syringe 18 withinhousing 11 is moved in a proximal direction relative to housing 11. Thisproximal movement can be achieved by using a retraction spring (notshown), located in distal region D. A compressed retraction spring, whenactivated, can supply sufficient force to the syringe 18 to move it in aproximal direction. Following sufficient retraction, any relativemovement between needle 17 and housing 11 can be locked with a lockingmechanism. In addition, button 13 or other components of device 10 canbe locked as required.

FIG. 2A and FIG. 2B show an example injection device 20 that includes asyringe 18, similar to as described above with reference to FIG. 1A andFIG. 1B. The injection device 20 of FIG. 2A also includes a housing (notshown).

As illustrated, the injection device 20 also includes a plunger 21 thatacts on the bung 14 to move the bung 14 into the syringe 18 and dispensemedicament through the needle 17. A drive spring 22 is provided to pushthe plunger 21 against the bung 14 and into the syringe 18 during use ofthe injection device 20. The drive spring 22 may be pre-loaded, and arelease mechanism may be provided to release the plunger 21 such thatthe drive spring 22 can push the plunger 21 and bung 14 to dispensemedicament, as described previously. It will be appreciated that thebung 14 may be omitted and the end 23 of the plunger 21 may act as abung within the syringe 18.

The injection device 20 of FIG. 2A also includes a delay mechanism thatprovides delayed user feedback at a time after the plunger 21 has movedinto the syringe 18. This delayed feedback informs the user that themedicament has been dispensed, and the delay provides time for themedicament to have dispersed from the injection site.

As illustrated, the injection device 20 of this example includes adamper, in this example a piston 24 and fluid chamber 25 that arelocated within the plunger 21. The plunger 21 is elongate and has acylindrical bore 26 with an opening 27 at the distal end of the plunger21, in which the piston 24 and fluid chamber 25 are located.

As shown, the piston 24 of this example is formed of a disc 28 and anopposite end 29, and a web 30 connecting the disc 28 and the oppositeend 29. The web 30 provides free space in the area surrounding the web30 between the disc 28 and the opposite end 29. Also provided is asealing plate 31 fixed in the cylindrical bore 26, including a seal 32.The sealing plate 31 includes an aperture through which the web 30 ofthe piston 24 extends, such that the disc 28 is on a first (proximal)side of the sealing plate 31 and the opposite end 29 is on a second(distal) side of the sealing plate 31. The fluid chamber 25 is definedbetween the sealing plate 31 and the end of the cylindrical bore 26within the plunger 21.

In this way, the disc 28 is located within the fluid chamber 25. Thedrive spring 22 acts between the opposite end 29 of the piston 24 andthe housing (not shown) of the injection device 20. The drive spring 22pushes the piston 24 towards the fluid chamber 25.

An indicator, in this example a sound generator 33, is located betweenthe sealing plate 31 and the opposite end 29 of the piston 24. In thisexample, the sound generator 33 is fixed to the proximal side of thesealing plate 31, but it may alternatively be fixed to the piston 24.The sound generator 33 comprises a pre-stressed member that generates asound when deflected (as explained below), which provides the user withan audible indication.

During use of the injection device 20 the drive spring 22 pushes thepiston 24, which in turn applies a compressive force to the fluidchamber 25, which in turn urges the plunger 21 against the bung 14 andinto the syringe 18. That is, the force of the drive spring 22 isprovided to the plunger 21 via the piston 24 and fluid chamber 25.

The disc 28 of the piston 24 is provided with at least one orifice 34through which the fluid in the fluid chamber 25 passes as the piston 24is urged in a proximal direction by the drive spring 22. The orifice(s)34 allows fluid to pass through the disc 28, from a proximal side to adistal side, and therefore allows the piston 24 to move proximally. Asthe piston 24 moves proximally, the web 30 slides within the aperture ofthe sealing plate 31 and fluid gradually moves into the space betweenthe sealing plate 31 and the disc 28 of the piston 24.

The orifice(s) 34 is of restricted size to limit the rate at which fluidcan pass through the orifice(s) 34 as the drive spring 22 pushes againstthe piston 24. The orifice(s) 34 thereby form a damper that dampsmovement of the piston 24 into the fluid chamber 25.

The rate at which the piston 24 is able to move in a proximal directiondepends on the rate at which the fluid can pass through the orifice(s)34, which is dependent on the viscosity of the fluid and the size andnumber of the orifice(s) 34, as well as the force applied by the drivespring 22.

As illustrated in FIG. 2B, when the piston 24 has moved completely oralmost completely into the fluid chamber 25 the sound generator 33 isdeflected by the opposite end 29 and/or the sealing plate 31. Deflectionof the sound generator 33 creates an audible sound that provides theuser with an indication.

In this example, the rate of fluid movement through the orifice(s) 34 isconfigured such that the piston 24 reaches the point at which the soundgenerator 33 is deflected at a time after the plunger 21 has reached theend of its movement into the syringe 18. In particular, for the givenforce of the drive spring 22 the time taken for the bung 14 to be pushedinto the syringe 18 is less than the time taken for the piston 24 to bepushed into the fluid chamber 25 and the sound generator 33 to bedeflected.

Therefore, the user is provided with the indication at a time after themedicament has been dispensed from the syringe 18. This delayed feedbackprovides for dispersion of the medicament from the injection site.

The duration of the delay may be, for example, more than 2 seconds, ormore than 5 seconds, or more than 10 seconds, or between 10 and 30seconds, or between 10 and 20 seconds.

FIG. 3A and FIG. 3B show an example injection device 35 that is similarto that described with reference to FIG. 2A and FIG. 2B. In thisexample, the injection device 35 also has a locking mechanism that holdsthe piston 24 in a locked position until the plunger 21 and bung 14 havebeen moved a pre-determined distance into the syringe 18.

The locking mechanism includes locking arms 36 that are pivotallyattached to the plunger 21 at pivots 38 and engage a distal side of theopposite end 29 of the piston 24, as shown in FIG. 3A and FIG. 3B. Astop 37 is provided for each locking arm 36, the stops 37 being locatedon the plunger 21 and the stops 37 are arranged to prevent rotation ofthe locking arms 36 as the plunger 21 and bung 14 are moved into thesyringe 18.

In particular, as the drive spring 22 acts on the piston 24 force istransferred to the plunger 21 via the locking arms 36 and stops 37,rather than via the disc 28 and fluid chamber 25. Therefore, the lockingarms 36 remain in the position illustrated in FIG. 3A and FIG. 3B whilethe plunger 21 and bung 14 move into the syringe 18 to dispensemedicament.

At or towards the end of the movement of the plunger 21 into the syringe18 the locking arms 36 abut against the annular end 39 of the syringe18. The leverage caused by the locking arms 36 abutting against theannular end 39 of the syringe 18 causes the locking arms 36 to eitherbreak or deform the stops 37, allowing the locking arms 36 to rotate andrelease the engagement between the piston 24 and plunger 21. Thereafter,the force of the drive spring 22 acts to push the piston 24 into thefluid chamber 25, eventually triggering the sound generator 33 after adelay caused by the damper (orifice(s) 34), as described with referenceto FIG. 2A and FIG. 2B.

The locking mechanism thereby prevents movement of the piston 24 untilthe plunger 21 has dispensed all or most of the medicament through theneedle 17. This is advantageous as it removes the variations in time forthe fluid to pass through the orifice(s) 34 in the disc 28, which may becaused by temperature and back pressure differences.

In an alternative example, the locking arms 36 may not be pivotallymounted, but may themselves be broken or deformed when they contact theannular end 39 of the syringe 18, thereby allowing the piston 24 to moveindependently of the plunger 21.

FIG. 4 shows an alternative example injection device 40 that includes asyringe 18 and a bung 14, similar to as described above with referenceto FIG. 2A, FIG. 2B, and FIG. 3.

The injection device 40 of this example also comprises a drive spring 22that acts on a piston 41 which in turn acts on a plunger 42 to drive theplunger 42 into the syringe 18. A locking mechanism locks in the piston41 to the plunger 42 until the plunger 42 has moved into the syringe 18,in the same way as described above with reference to FIG. 3. Inparticular, locking arms 36 are pivotally attached to the plunger 42 atpivots 38 and engage with the piston 41 until they contact the annularend 39 of the syringe 18. At this point, the stops 37 are broken and thelocking arms 36 can rotate and release the piston 41 from the plunger42. Thereafter, the drive spring 22 acts to push the piston 41 into afluid chamber 25 formed within a cylindrical bore 43 of the plunger 42and closed by a sealing plate 31.

The sealing plate 31 is located in the plunger 42 and the piston 41includes a web 44 that passes through an aperture in the sealing plate31, similarly to the example of FIG. 3A and FIG. 3B. The drive spring 22abuts against a proximal end 45 of the piston 41, and a sound generator33, in this example a pre-stressed member, is located between theproximal end 45 and the sealing plate 31. The distal end of the piston41, located in the fluid reservoir 25, includes a damper in the form ofa rotary agitator 46.

The rotary agitator 46 comprises one or more fins, paddles, or angledplates that create resistance as the rotary agitator 46 rotates withinthe fluid in the fluid chamber 25.

The proximal end 45 of the piston 41 includes at least one protrusion 47that engages with a thread 48 formed in the cylindrical bore 43 of theplunger 42. The thread 48 is helical along the cylindrical bore 43, andso to move axially within the injection device 40 the piston 41 mustrotate so that the protrusion(s) 47 move along the thread 48.

Therefore, after the locking arms 36 have released the piston 41 fromthe plunger 42, and the drive spring 22 is pushing the piston 41 in adistal direction, the piston 41 rotates within the plunger 42. Thisrotation is damped by the rotation of the rotary agitator 46 within thefluid chamber 25. This resistance delays the progress of the piston 41in a distal direction.

Once the piston 41 has been pushed/rotated towards the end of the fluidchamber 25 the sound generator 33 is compressed between the proximal end45 of the piston 41 and the sealing plate 31, and is deflected. Thesound generator generates an audible sound as it is deflected, providingthe user with an audible indication.

The duration of the delay between the start of the movement of thepiston 41 and the compression of the sound generator 33 may be, forexample, more than 2 seconds, or more than 5 seconds, or more than 10seconds, or between 10 and 30 seconds, or between 10 and 20 seconds.

In this example, the piston 41 only starts moving into the fluid chamber25 after the bung 14 is at or near the end of the syringe 18, and so theindication is provided to the user at a time after the medicament hasbeen injected. This allows time for the medicament to disperse from theinjection site.

In an alternative example, the locking mechanism (locking arms) areomitted, and the damping provided by the rotary agitator 46 and fluidchamber 25 is increased such that, for a given force from the drivespring 22, the time taken for the piston 41 to move from the initialposition to the position in which the sound generator 33 is triggered isgreater than the time required to move the bung 14 to the end of thesyringe 18 and dispense all of the medicament. In this way, the audibleindication is provided at a time after the medicament has beendispensed, allowing for dispersal of the medicament from the injectionsite.

FIG. 5A shows an alternative example injection device 50 that includes abung 14 and syringe 18, similar to as described previously. Inparticular, the injection device 50 has a syringe 18 and a bung 14 thatis pushed into the syringe 18 by a plunger 51. In this example, a piston52 is located between the plunger 51 and the bung 14, and the piston 52is received in a recess 53 in the distal end 54 of the plunger 51. Afluid chamber 25 is defined in the recess 53 and the piston 52 seals thefluid chamber 25. The drive spring 22 urges the plunger 51 against thepiston 52, which in turn is urged against the bung 14.

The plunger 51 includes a cylindrical bore 55 extending from theproximal end 56 of the plunger 51, and the recess 53 is located in thedistal end 54 of the plunger 51. A wall 57 separates the cylindricalbore 55 and the recess 53 and the wall 57 includes at least one orifice58 through which fluid passes as the piston 52 moves into the recess 53to compress the fluid chamber 25. The fluid in the fluid chamber 25 andorifice 58 create a damper that damps movement of the piston 52 into thefluid chamber 25.

On the proximal side of the wall 57 (opposite to the fluid chamber 25)is a spacer 59 that defines a recipient chamber 60 that is in fluidcommunication with the orifice 58, such that fluid passing from thefluid chamber 25 through the orifice 58 passes into the recipientchamber 60. The recipient chamber 60 includes an air outlet 61 so thatthe air displaced by the fluid can escape. The drive spring 22 pushes onthe spacer 59 and in turn the wall 57, and so drives the plunger 51towards the bung 14 and piston 52. In so doing the piston 52 is movedinto the fluid chamber 25 and fluid is forced through the orifice 58into the recipient chamber 60. The rate of movement of fluid through theorifice 58 determines the rate at which the piston 52 moves into therecess 53. Therefore, by defining the fluid viscosity and size andnumber of orifices 58, the rate at which the piston 52 moves into therecess 53 can be defined.

The injection device 50 of this example also includes an indicator, inthis example a sound generator. As illustrated, the sound generatorincludes a pre-stressed member 62 that is located on the plunger 51 andmoves with the plunger 51 as the plunger 51 moves towards the syringe18.

As illustrated, the plunger 51 also includes a clip 63 that holds thepre-stressed member 62 in a first state as the plunger 51 moves into thesyringe 18. The clip includes an arm 64 and a head 65, and the head 65is in contact with, and urged against, the side of the piston 52. Thehead 65 may be urged against the side of the piston 52 by a biasingmember (not shown) or by the force provided by the pre-stressed member62.

The piston 52 includes a notch 66 adapted to receive the head 65 of theclip 63 once the piston 52 has moved a pre-determined distance into thefluid chamber 25. As illustrated in FIG. 5A, in an initial position thehead 65 of the clip 63 is located proximally of the notch 66, and as thedrive spring 22 causes the piston 52 to move into the fluid chamber 25the head 65 and notch 66 come into alignment, as shown in FIG. 5B. Oncealigned, the arm 64 deflects inwards and the pre-stressed member 62 isdeflected, generating an audible sound that provides an indication tothe user.

The viscosity of the fluid and the size and number of orifices 58 areselected such that the drive spring 22 pushes the bung 14 completelyinto the syringe 18, to dispense all of the medicament, before thepiston 52 reaches the point at which the audible indication isgenerated. In this way, the feedback is provided at a time after themedicament has been injected, allowing for the medicament to dispersefrom the injection site.

The arrangement of the damper creates a delay between the start of themovement of the piston 52 into the fluid chamber 25, and the time atwhich the sound generator 62 generates a sound. The duration of thedelay may be, for example, more than 2 seconds, or more than 5 seconds,or more than 10 seconds, or between 10 and 30 seconds, or between 10 and20 seconds.

FIG. 6A shows an alternative example injection device 70 similar to theexample described with reference to FIG. 5. In particular, the injectiondevice 70 has a syringe 18 and a bung 14 that is pushed into the syringe18 by a plunger 71. A piston 72 is located between the plunger 71 andthe bung 14, and the piston 72 is received in a recess 73 in the distalend 74 of the plunger 71. The recess 73 forms a fluid chamber 25 and thepiston 72 seals the fluid chamber 25.

The plunger 71 includes a cylindrical bore 75 extending from theproximal end 76 of the plunger 71, and the recess 73 is located in thedistal end 74 of the plunger 71. A wall 77 separates the cylindricalbore 75 and the recess 73, and the wall 77 includes an orifice 78through which fluid passes as the piston 72 moves into the fluid chamber25.

An elongate recipient chamber 79 is formed on the proximal side of thewall 79 (opposite to the fluid chamber 25), such that fluid passing fromthe fluid chamber 25 through the orifice 78 passes into the recipientchamber 79. A slider 80 is located within the elongate recipient chamber79 and the slider 80 is initially in a distal position, proximate to thewall 77.

The drive spring 22 pushes on the wall 77 and so drives the plunger 71towards the bung 14 and syringe 18. In so doing the piston 72 is movedinto the fluid chamber 25 and fluid is forced through the orifice 78into the elongate recipient chamber 79. The rate of movement through theorifice 78 defines the rate at which the piston 72 moves into the fluidchamber 25. Therefore, by defining the fluid viscosity and size andnumber of orifices 78, the rate at which the piston 72 moves into thefluid chamber 25 can be defined.

The injection device 70 of this example also includes an indicator, inthis example a sound generator. As illustrated, the sound generatorincludes a pre-stressed member 81 that is located at the proximal end ofthe elongate recipient chamber 79, opposite to the orifice 78. Thepre-stressed member 81 is initially in deflected state, as shown in FIG.6A.

As the drive spring 22 pushes the plunger 71 against the piston 72 andbung 14 the piston 72 gradually moves into the fluid chamber 25 andfluid is pushed through the orifice 78 into the elongate recipientchamber 79. As fluid passes into the elongate recipient chamber 79 itpushes the slider 80 in a proximal direction, towards the pre-stressedmember 81. Eventually, as shown in FIG. 6B, the slider 80 contacts thepre-stressed member 81 and deflects the pre-stressed member 81,generating an audible sound which provides an indication to the user.

The viscosity of the fluid and the size of the orifice 78 can beselected such that the drive spring 22 pushes the bung 14 completelyinto the syringe 18, to dispense all of the medicament, before theslider 80 reaches the pre-stressed element 81. In this way, there is adelay between time at which the medicament has been completely dispensedand the time at which the sound generator 81 is contacted by the slider80, allowing time for the medicament to disperse from the injectionsite.

The duration of the delay may be, for example, more than 2 seconds, ormore than 5 seconds, or more than 10 seconds, or between 10 and 30seconds, or between 10 and 20 seconds.

FIG. 7A and FIG. 7B show a further example injection device 82. Theinjection device 82 includes a plunger 83, a carrier 84, and rotatablelocking arms 85 that hold the carrier 84 until the plunger 83 has beenmoved a distance into the syringe (not shown). As shown in FIG. 7B, oncethe carrier 84 is released the drive spring 22 urges the carrier 84 in aproximal direction.

The locking arms 85 are pivotally mounted to the housing 87 of theinjection device 82 at pivots 86. The locking arms 85 include deflectedends 88 that hold the carrier 84 as the drive spring 22 pushes againstthe carrier 84. In the initial position, shown in FIG. 7A, the lockingarms are prevented from rotating by the presence of the plunger 83. Asshown in FIG. 7B, once the drive spring 22 has moved the plunger 83 intothe syringe (not shown), the arms 83 can rotate and release the carrier84.

In this example, the proximal end 89 of the housing 87 has a cylindricalprotrusion 90 and a piston 91 is provided within the cylindricalprotrusion 90 to define a fluid chamber 92. A seal 93 is providedbetween the piston 91 and the cylindrical protrusion 90. The proximalend 89 of the housing 87, within the cylindrical protrusion 90, includesan orifice 94. A second chamber 95 is provided on the opposite side ofthe orifice 94 to the fluid chamber 92. The second chamber 95 isoptionally provided with an air outlet 96.

As shown in FIG. 7B, when the carrier 84 is released by the locking arms84, after the plunger 83 has moved distally, the drive spring 22 urgesthe carrier 84 against the piston 91, which is pushed into the fluidchamber 92 and urges fluid through the orifice 94 and into the secondchamber 95. Air may be displaced from the second chamber 95 through theair outlet 96.

A seal 97 may initially be provided over the orifice 94 to preventmovement of the fluid into the second chamber 95 before the carrier 84has been released.

The second chamber 95 may additionally be transparent, so that the usercan see the fluid entering the second chamber 95 as an indication thatthe plunger 83 has completed its movement into the syringe (not shown).The fluid may be coloured. The fluid may be a liquid, for example water.

The orifice 94 damps movement of the piston 91 into the fluid chamber92.

As illustrated in FIG. 7A and FIG. 7B, the piston 91 may trigger anaudible indication to the user. In this example, the piston 91 comprisesan arm 98 that protrudes from the piston 91 and engages a soundgenerator. The sound generator is a pre-stressed element 99 that is heldin a deflected position by the arm 98 until the piston 91 moves into thefluid chamber 92, at which point the arm 98 disengages the pre-stressedelement 99, which returns to its natural shape. This changing of shapeof the pre-stressed element 99 generates an audible sound, whichprovides the user with an indication that enough time has elapsed forthe medicament to have dispersed from the injection site. In particularthe arm 98 does not disengage the pre-stressed element 99 until a volumeof fluid has passed into the second chamber 95, which is delayed by thedamping action of the orifice 94, thereby providing a delay in thefeedback. The duration of the delay may be, for example, more than 2seconds, or more than 5 seconds, or more than 10 seconds, or between 10and 30 seconds, or between 10 and 20 seconds.

The locking arms 85 only release the carrier 84 after the plunger 83 hasbeen moved a pre-determined distance into the syringe (not shown), andthe arrangement of the piston 91, fluid chamber 92 and pre-stressedelement 99 then creates a further delay before the audible indication isgenerated, providing time for the medicament to disperse from theinjection site. In any of the above-described injection devices it willbe appreciated that the drive spring may be omitted if the injectiondevice is adapted to be manually operated. For example, the injectiondevice may be provided with a lever or button that the user manuallyoperates to push the plunger into the syringe. In this case, the forceprovided by the user may be used to compress the fluid reservoir.

In any of the above-described examples, the damping effect that providesthe delay before the feedback is generated may be increased by using ahighly viscous, or non-Newtonian fluid. This reduces the rate at whichthe fluid can pass through the outlet during compression of the fluidreservoir.

The terms “drug” or “medicament” are used herein to describe one or morepharmaceutically active compounds. As described below, a drug ormedicament can include at least one small or large molecule, orcombinations thereof, in various types of formulations, for thetreatment of one or more diseases. Exemplary pharmaceutically activecompounds may include small molecules; polypeptides, peptides andproteins (e.g., hormones, growth factors, antibodies, antibodyfragments, and enzymes); carbohydrates and polysaccharides; and nucleicacids, double or single stranded DNA (including naked and cDNA), RNA,antisense nucleic acids such as antisense DNA and RNA, small interferingRNA (siRNA), ribozymes, genes, and oligonucleotides. Nucleic acids maybe incorporated into molecular delivery systems such as vectors,plasmids, or liposomes. Mixtures of one or more of these drugs are alsocontemplated.

The term “drug delivery device” shall encompass any type of device orsystem configured to dispense a drug into a human or animal body.Without limitation, a drug delivery device may be an injection device(e.g., syringe, pen injector, auto injector, large-volume device, pump,perfusion system, or other device configured for intraocular,subcutaneous, intramuscular, or intravascular delivery), skin patch(e.g., osmotic, chemical, micro-needle), inhaler (e.g., nasal orpulmonary), implantable (e.g., coated stent, capsule), or feedingsystems for the gastro-intestinal tract. The presently described drugsmay be particularly useful with injection devices that include a needle,e.g., a small gauge needle.

The drug or medicament may be contained in a primary package or “drugcontainer” adapted for use with a drug delivery device. The drugcontainer may be, e.g., a cartridge, syringe, reservoir, or other vesselconfigured to provide a suitable chamber for storage (e.g., short- orlong-term storage) of one or more pharmaceutically active compounds. Forexample, in some instances, the chamber may be designed to store a drugfor at least one day (e.g., 1 to at least 30 days). In some instances,the chamber may be designed to store a drug for about 1 month to about 2years. Storage may occur at room temperature (e.g., about 20° C.), orrefrigerated temperatures (e.g., from about −4° C. to about 4° C.). Insome instances, the drug container may be or may include a dual-chambercartridge configured to store two or more components of a drugformulation (e.g., a drug and a diluent, or two different types ofdrugs) separately, one in each chamber. In such instances, the twochambers of the dual-chamber cartridge may be configured to allow mixingbetween the two or more components of the drug or medicament prior toand/or during dispensing into the human or animal body. For example, thetwo chambers may be configured such that they are in fluid communicationwith each other (e.g., by way of a conduit between the two chambers) andallow mixing of the two components when desired by a user prior todispensing. Alternatively or in addition, the two chambers may beconfigured to allow mixing as the components are being dispensed intothe human or animal body.

The drug delivery devices and drugs described herein can be used for thetreatment and/or prophylaxis of many different types of disorders.Exemplary disorders include, e.g., diabetes mellitus or complicationsassociated with diabetes mellitus such as diabetic retinopathy,thromboembolism disorders such as deep vein or pulmonarythromboembolism. Further exemplary disorders are acute coronary syndrome(ACS), angina, myocardial infarction, cancer, macular degeneration,inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis.

Exemplary drugs for the treatment and/or prophylaxis of diabetesmellitus or complications associated with diabetes mellitus include aninsulin, e.g., human insulin, or a human insulin analogue or derivative,a glucagon-like peptide (GLP-1), GLP-1 analogues or GLP-1 receptoragonists, or an analogue or derivative thereof, a dipeptidyl peptidase-4(DPP4) inhibitor, or a pharmaceutically acceptable salt or solvatethereof, or any mixture thereof. As used herein, the term “derivative”refers to any substance which is sufficiently structurally similar tothe original substance so as to have substantially similar functionalityor activity (e.g., therapeutic effectiveness).

Exemplary insulin analogues are Gly(A21), Arg(B31), Arg(B32) humaninsulin (insulin glargine); Lys(B3), Glu(B29) human insulin; Lys(B28),Pro(B29) human insulin; Asp(B28) human insulin; human insulin, whereinproline in position B28 is replaced by Asp, Lys, Leu, Val or Ala andwherein in position B29 Lys may be replaced by Pro; Ala(B26) humaninsulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30)human insulin.

Exemplary insulin derivatives are, for example, B29-N-myristoyl-des(B30)human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoylhuman insulin; B29-N-palmitoyl human insulin; B28-N-myristoylLysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-gamma-glutamyl)-des(B30) humaninsulin; B29-N-(N-lithocholyl-gamma-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(co-carboxyhepta¬decanoyl) human insulin. Exemplary GLP-1, GLP-1analogues and GLP-1 receptor agonists are, for example:Lixisenatide/AVE0010/ZP10/Lyxumia,Exenatide/Exendin-4/Byetta/Bydureon/ITCA 650/AC-2993 (a 39 amino acidpeptide which is produced by the salivary glands of the Gila monster),Liraglutide/Victoza, Semaglutide, Taspoglutide, Syncria/Albiglutide,Dulaglutide, rExendin-4, CJC-1134-PC, PB-1023, TTP-054,Langlenatide/HM-11260C, CM-3, GLP-1 Eligen, ORMD-0901, NN-9924, NN-9926,NN-9927, Nodexen, Viador-GLP-1, CVX-096, ZYOG-1, ZYD-1, GSK-2374697,DA-3091, MAR-701, MAR709, ZP-2929, ZP-3022, TT-401, BHM-034. MOD-6030,CAM-2036, DA-15864, ARI-2651, ARI-2255, Exenatide-XTEN andGlucagon-Xten.

An exemplary oligonucleotide is, for example: mipomersen/Kynamro, acholesterol-reducing antisense therapeutic for the treatment of familialhypercholesterolemia.

Exemplary DPP4 inhibitors are Vildagliptin, Sitagliptin, Denagliptin,Saxagliptin, Berberine.

Exemplary hormones include hypophysis hormones or hypothalamus hormonesor regulatory active peptides and their antagonists, such asGonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin),Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin,Triptorelin, Leuprorelin, Buserelin, Nafarelin, and Goserelin.

Exemplary polysaccharides include a glucosaminoglycane, a hyaluronicacid, a heparin, a low molecular weight heparin or an ultra-lowmolecular weight heparin or a derivative thereof, or a sulphatedpolysaccharide, e.g. a poly-sulphated form of the above-mentionedpolysaccharides, and/or a pharmaceutically acceptable salt thereof. Anexample of a pharmaceutically acceptable salt of a poly-sulphated lowmolecular weight heparin is enoxaparin sodium. An example of ahyaluronic acid derivative is Hylan G-F 20/Synvisc, a sodiumhyaluronate.

The term “antibody”, as used herein, refers to an immunoglobulinmolecule or an antigen-binding portion thereof. Examples ofantigen-binding portions of immunoglobulin molecules include F(ab) andF(ab′)2 fragments, which retain the ability to bind antigen. Theantibody can be polyclonal, monoclonal, recombinant, chimeric,de-immunized or humanized, fully human, non-human, (e.g., murine), orsingle chain antibody. In some embodiments, the antibody has effectorfunction and can fix complement. In some embodiments, the antibody hasreduced or no ability to bind an Fc receptor. For example, the antibodycan be an isotype or subtype, an antibody fragment or mutant, which doesnot support binding to an Fc receptor, e.g., it has a mutagenized ordeleted Fc receptor binding region.

The terms “fragment” or “antibody fragment” refer to a polypeptidederived from an antibody polypeptide molecule (e.g., an antibody heavyand/or light chain polypeptide) that does not comprise a full-lengthantibody polypeptide, but that still comprises at least a portion of afull-length antibody polypeptide that is capable of binding to anantigen. Antibody fragments can comprise a cleaved portion of a fulllength antibody polypeptide, although the term is not limited to suchcleaved fragments. Antibody fragments that are useful include, forexample, Fab fragments, F(ab′)2 fragments, scFv (single-chain Fv)fragments, linear antibodies, monospecific or multispecific antibodyfragments such as bispecific, trispecific, and multispecific antibodies(e.g., diabodies, triabodies, tetrabodies), minibodies, chelatingrecombinant antibodies, tribodies or bibodies, intrabodies, nanobodies,small modular immunopharmaceuticals (SMIP), binding-domainimmunoglobulin fusion proteins, camelized antibodies, and VHh containingantibodies. Additional examples of antigen-binding antibody fragmentsare known in the art.

The terms “Complementarity-determining region” or “CDR” refer to shortpolypeptide sequences within the variable region of both heavy and lightchain polypeptides that are primarily responsible for mediating specificantigen recognition. The term “framework region” refers to amino acidsequences within the variable region of both heavy and light chainpolypeptides that are not CDR sequences, and are primarily responsiblefor maintaining correct positioning of the CDR sequences to permitantigen binding. Although the framework regions themselves typically donot directly participate in antigen binding, as is known in the art,certain residues within the framework regions of certain antibodies candirectly participate in antigen binding or can affect the ability of oneor more amino acids in CDRs to interact with antigen.

Exemplary antibodies are anti PCSK-9 mAb (e.g., Alirocumab), anti IL-6mAb (e.g., Sarilumab), and anti IL-4 mAb (e.g., Dupilumab).

The compounds described herein may be used in pharmaceuticalformulations comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds may also be used in pharmaceutical formulations thatinclude one or more other active pharmaceutical ingredients or inpharmaceutical formulations in which the present compound or apharmaceutically acceptable salt thereof is the only active ingredient.Accordingly, the pharmaceutical formulations of the present disclosureencompass any formulation made by admixing a compound described hereinand a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salts of any drug described herein are alsocontemplated for use in drug delivery devices. Pharmaceuticallyacceptable salts are for example acid addition salts and basic salts.Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g.salts having a cation selected from an alkali or alkaline earth metal,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1 C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are known to those of skill in thearts.

Pharmaceutically acceptable solvates are for example hydrates oralkanolates such as methanolates or ethanolates.

Those of skill in the art will understand that modifications (additionsand/or removals) of various components of the substances, formulations,apparatuses, methods, systems and embodiments described herein may bemade without departing from the full scope and spirit of the presentinvention, which encompass such modifications and any and allequivalents thereof.

1. A feedback mechanism for an injection device, the injection deviceconfigured to deliver a medicament to a user, the feedback mechanismcomprising: a piston; a fluid chamber, wherein the piston is configuredto move into the fluid chamber during use of the injection device; adamper configured to damp movement of the piston; and an indicatorconfigured to provide feedback to the user after the piston has moved apredetermined distance into the fluid chamber.
 2. The feedback mechanismof claim 1, further comprising a biasing member configured to urge thepiston into the fluid chamber.
 3. The feedback mechanism of claim 1,wherein the damper comprises a rotary agitator disposed within the fluidchamber, and wherein movement of the piston into the fluid chambercauses rotation of the rotary agitator such that the movement of thepiston is damped by the rotary agitator.
 4. The feedback mechanism ofclaim 3, wherein the rotary agitator comprises one or more of fins,paddles, or angled plates that are configured to rotate within a fluidof the fluid chamber.
 5. The feedback mechanism of claim 3, wherein thepiston comprises the rotary agitator.
 6. The feedback mechanism of claim5, wherein a distal end of the piston comprises the rotary agitator. 7.The feedback mechanism of claim 3, wherein the piston comprises anoutward protrusion configured to engage a helical thread formed in acylindrical bore of a plunger such that the movement of the piston intothe fluid chamber causes the outward protrusion to move along thehelical thread to rotate the piston.
 8. The feedback mechanism of claim1, wherein the piston comprises a plate that extends across the fluidchamber, and the damper comprises one or more orifices located in theplate through which fluid flows as the piston moves into the fluidchamber.
 9. The feedback mechanism of claim 1, further comprising arecipient chamber into which fluid is urged as the piston moves into thefluid chamber, and wherein the damper comprises an orifice arrangedbetween the fluid chamber and the recipient chamber.
 10. The feedbackmechanism of claim 9, wherein the recipient chamber comprises a sliderconfigured to be moved by fluid passing into the recipient chamber. 11.The feedback mechanism of claim 10, wherein the slider is configured toengage the indicator after the slider has moved a predetermined distanceto provide feedback to the user.
 12. The feedback mechanism of claim 11,wherein the indicator is a pre-stressed element configured to generatean audible sound when the slider engages the indicator after the sliderhas moved the predetermined distance.
 13. The feedback mechanism ofclaim 1, wherein the indicator is disposed between the piston and a partof the injection device, such that movement of the piston into the fluidchamber causes the indicator to be engaged by the piston, the indicatorproviding feedback to the user after being engaged by the piston. 14.The feedback mechanism of claim 1, wherein the indicator is disposedbetween the piston and a part of the injection device, such thatmovement of the piston into the fluid chamber causes the indicator to beengaged by the part of the injection device, the indicator providingfeedback to the user after being engaged by the part of the injectiondevice.
 15. The feedback mechanism of claim 1, wherein the indicatorcomprises a sound generator configured to generate an audible sound. 16.The feedback mechanism of claim 15, wherein the sound generatorcomprises a pre-stressed element configured to generate the audiblesound when deflected.
 17. The feedback mechanism of claim 16, whereinthe pre-stressed element is mounted to a plunger and arranged to bedeflected as the plunger moves to displace a medicament.
 18. Thefeedback mechanism of claim 17, wherein the plunger comprises an arm towhich the pre-stressed element is mounted.
 19. The feedback mechanism ofclaim 18, wherein the arm is arranged to engage the piston as the pistonmoves into the fluid chamber, the arm being arranged to deflect thepre-stressed element after engaging the piston.
 20. The feedbackmechanism of claim 1, wherein the piston is in direct contact with afluid within the fluid chamber, the fluid being distinct from amedicament within a reservoir of the injection device.